Long-Term Ketogenic Diet (22 Weeks) in Mice Leads to Weight Gain, Hepatic Steatosis and Impaired Glucose Tolerance

Ballieux, Bart EPB; Dijck, Laura van; Doelder, Rianne den; Koning, Eelco de

doi:10.1210/endo-meetings.2011.part3.p34.p3-397

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“…[11][12][13] However, KD-fed mice showed increased serum triacylglycerol and cholesterol levels along with a higher hepatic lipid accumulation, which possibly increased the ROS levels. 14,15 Moreover, some studies stated that KD induced nephrolithiasis, muscle cramps, bone fractures, and hepatic injury in mice. 16,17 Thus, the health risk imposed by the long-term use of KD for glycemic control in type 2 diabetic mice demands further investigation.…”

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confidence: 99%

<p>High-Intensity Interval Training Attenuates Ketogenic Diet-Induced Liver Fibrosis in Type 2 Diabetic Mice by Ameliorating TGF-β1/Smad Signaling</p>

Zhang¹,

Shen²,

Shen³

et al. 2020

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Ketogenic diet (KD) and high-intensity interval training (HIIT) have preclinical benefits for type 2 diabetes (Db). However, the health risks of long-term KD use in diabetes should be ascertained and prevented. We hypothesized that KD-induced liver fibrosis in type 2 diabetic mice could be ameliorated by HIIT. Methods: Streptozotocin-induced type 2 diabetic mice were divided into high-fat diet (HFD) control (Db+HFD+Sed), KD control (Db+KD+Sed), HFD coupled with HIIT (Db +HFD+HIIT), and KD coupled with HIIT (Db+KD+HIIT) groups (n=6, per group). Control mice were kept in sedentary (Sed), while HIIT group mice underwent 40-minute highintensity interval training three alternate days per week. After 8-week intervention, the indicators of body weight and insulin resistance, oxidative stress markers, hepatic fibrosis, genetic and protein expression of related pathways were tested. Results: We found that fasting blood glucose level was reduced in the Db+HFD+HIIT, Db +KD+Sed, and Db+KD+HIIT groups. Insulin sensitivity was increased in diabetic mice of these groups, whereas ROS levels were decreased in mice that underwent HIIT. The immunohistochemical staining of liver, serum index, and hepatic parameters of diabetic mice in the KD group revealed liver fibrosis, which was significantly attenuated by HIIT. Besides, these effects of HIIT were the outcome of hepatic stellate cell's inactivation, reduced protein expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases, and the inhibition of TGF-β1/Smad signaling. Conclusion: KD had a profound fibrotic effect on the liver of type 2 diabetic mice, whereas HIIT ameliorated this effect. KD did not show any apparent benefit as far as glucose tolerance and homeostasis were concerned. Concisely, our results demonstrated that KD should be coupled with HIIT for the prevention and preclinical mitigation of type 2 diabetes.

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